In 2016,Read, Cai; Fitzpatrick, Christopher M.; Yang, Peiran; Kuc, Rhoda E.; Maguire, Janet J.; Glen, Robert C.; Foster, Richard E.; Davenport, Anthony P. published 《Cardiac action of the first G protein biased small molecule apelin agonist》.Biochemical Pharmacology (Amsterdam, Netherlands) published the findings.Computed Properties of C8H6FNO4 The information in the text is summarized as follows:
Apelin peptide analogs displaying bias towards G protein signalling pathways have beneficial cardiovascular actions compared with the native peptide in humans in vivo. Our aim was to determine whether small mol. agonists could retain G protein bias. We have identified a biased small mol., CMF-019 (I), and characterised it in vitro and in vivo. In competition radioligand binding experiments in heart homogenates, CMF-019 bound to the human, rat and mouse apelin receptor with high affinity (pKi = 8.58 ± 0.04, 8.49 ± 0.04 and 8.71 ± 0.06 resp.). In cell-based functional assays, whereas, CMF-019 showed similar potency for the Gαi pathway to the endogenous agonist [Pyr1]apelin-13 (pD2 = 10.00 ± 0.13 vs 9.34 ± 0.15), in β-arrestin and internalisation assays it was less potent (pD2 = 6.65 ± 0.15 vs 8.65 ± 0.10 and pD2 = 6.16 ± 0.21 vs 9.28 ± 0.10 resp.). Anal. of these data demonstrated a bias of ∼400 for the Gαi over the β-arrestin pathway and ∼6000 over receptor internalisation. CMF-019 was tested for in vivo activity using i.v. injections into anesthetized male Sprague-Dawley rats fitted with a pressure-volume catheter in the left ventricle. CMF-019 caused a significant increase in cardiac contractility of 606 ± 112 mmHg/s (p < 0.001) at 500 nmol. CMF-019 is the first biased small mol. identified at the apelin receptor and increases cardiac contractility in vivo. We have demonstrated that Gαi over β-arrestin/internalisation bias can be retained in a non-peptide analog and predict that such bias will have the therapeutic benefit following chronic use. CMF-019 is suitable as a tool compound and provides the basis for design of biased agonists with improved pharmacokinetics for treatment of cardiovascular conditions such as pulmonary arterial hypertension. The experimental process involved the reaction of Methyl 4-fluoro-3-nitrobenzoate(cas: 329-59-9Computed Properties of C8H6FNO4)
Methyl 4-fluoro-3-nitrobenzoate(cas: 329-59-9) belongs to methyl benzoate. Methyl benzoate reacts at both the ring and the ester, depending on the substrate. Electrophiles attack the ring, illustrated by acid-catalysed nitration with nitric acid to give methyl 3-nitrobenzoate.Computed Properties of C8H6FNO4Methyl 4-fluoro-3-nitrobenzoate is used to prepare dimethyl 3-nitro-3′,4-oxydibenzoate by reacting with 3-hydroxy-benzoic acid methyl ester.
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